ABSTRACT: Atrial fibrillation is a heritable cardiovascular condition that increases risk for death, stroke, and congestive heart failure. We will perform large-scale human genetic discovery to identify novel genes and genetic variants associated with atrial fibrillation, other cardiovascular diseases, and related quantitative traits. We will also perform functional follow-up in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Our research team combines expertise in high-throughput genetics and genomics, bioinformatics, computational and statistical genetics methods development, and molecular mechanisms of cardiac arrhythmias. We will identify a comprehensive set of genetic variants of all frequencies by performing deep whole genome sequencing on 2,000 individuals including 1,000 early-onset cases of atrial fibrillation and 1,000 age- and sex- matched healthy controls. This will allow for association tests between nearly all genomic variants in these individuals and atrial fibrillation. We will also leverage recently generated GWAS data from three large biorepositories by imputing variants discovered by sequencing into 7,667 AF cases and > 90,000 controls. This will enable association testing of the vast majority of genomic variation, including rare, low frequency and common variants, indels and structural variants in a much larger sample of AF cases and controls. We will also examine additional cardiovascular-related diseases and traits: stroke, congestive heart failure, blood pressure, heart rate, and C-reactive protein in 71,312 samples with ancestry matched to the sequenced individuals. Lastly, we will perform molecular follow-up of novel genes and genetic variants in a highly innovative experimental model. We will up and down regulate newly identified genes and introduce variants associated with AF into human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CM), a differentiated cell-line with the ability to recapitulate heart beats in 96-well plates. We will then assess the impact on quantifiable traits that reflect function in vivo, including properties of ion channel function, beating frequency and electrical impulse propogation. The proposed interdisciplinary studies will provide new insights into AF mechanisms that have the potential to catalyze breakthroughs in prevention, treatment, and diagnosis of CVDs with broad applicability to many traits and diseases.